The present invention relates to novel aminoazetidine, -pyrrolidine and -piperidine derivatives, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions. The present compounds show a high and selective binding affinity to the histamine H3 receptor indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment of diseases and disorders related to the histamine H3 receptor.
The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments (see eg Stark et al., Drugs Fut. 1996, 21, 507-520; Leurs et al., Progress in Drug Research 1995, 45, 107-165). Recently, the human histamine H3 receptor has been cloned, cf Lovenberg et al, Molecular Pharmacology, June 1999, 55, 1101-1107. The histamine H3 receptor is a presynaptic autoreceptor located both in the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evidence suggests that the H3 receptor shows intrinsic, constitutive activity, in vitro as well as in vivo (ie it is active in the absence of an agonist; see eg Morisset et al., Nature 2000, 408, 860-864). Compounds acting as inverse agonists can inhibit this activity. The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists could be important mediators of neuronal activity. Accordingly, the histamine H3 receptor is an important target for new therapeutics.
Compounds similar to the compounds of the present invention have previously been disclosed, cf U.S. Pat. No. 3,963,745, U.S. Pat. No. 3,966,957, DE 25 58 348, U.S. Pat. No. 6,090,802, WO 97/23483, WO 97/09308, JP 07048375, EP 518 558, Acta Pharm Suec. Suppl. 1, 200-218, 1983, Life Sci., 32(25), 2877-2886, 1983, U.S. Pat. No. 4,109,005, BE 861790, Aviat. Space Environ. Med., 48(9), 867-871, 1977, U.S. Pat. No. 4,049,821, U.S. Pat. No. 4,039,678, Therapie 1977, 32(1), 121-132, U.S. Pat. No. 4,002,757 DE 19 64 516, NL 6500326, U.S. Pat. No. 3,787,419, Irikura, Yakugaku Zasshi 1962, 82, 356, DE 24 61 802, Eur. J. Chem. Chim. Ther. 1982, 17, 437, J. Med. Chem. 1992, 35, 4334, Chem. Pharm. Bull. 1995, 43, 947, Arzneim. Forsch. 1999, 49, 96, U.S. Pat. No. 5,571,832, NIDA Res. Monogr. 1993, 140 (Problems of Drug Dependence, volume 1), 179-195. However, these references neither disclose nor suggest that these compounds may have a histamine H3 receptor antagonistic or agonistic activity.
Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Most of these are imidazole derivatives (see eg Stark et al., Drugs of the Future 1996, 21, 507-520; Tozer, Kalinddjian, Expert Opinion on Therapeutic Patents 2000, 10, 1045-1055). However, recently some imidazole-free ligands of the histamine H3 receptor have been described (see eg Walczynski et al., Arch. Pharm. Pharm. Med. Chem. 1999, 332, 389-398; Linney et al., J. Med. Chem. 2000, 43, 2362-2370; Ganellin et al., Arch. Pharm. Pharm. Med. Chem. 1998, 331, 395-404; Walczynski et al., II Farmaco 1999, 54, 684-694; WO 99/42458, EP 0 978 512, WO 97/17345, U.S. Pat. No. 6,316,475, WO 01/66534, WO 01/74810, WO 01/44191, WO 01/74815, WO 01/74773, WO 01/74813, WO 01/74814 and WO 02/12190.
However, these compounds differ structurally from the present compounds.
In view of the art""s interest in histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that a novel class of aminoazetidine, -pyrrolidine and -piperidine derivatives has a high and specific affinity to and potency at the histamine H3 receptor.
Due to their interaction with the histamine H3 receptor, the present compounds are useful in the treatment of a wide range of conditions and disorders in which an interaction with the histamine H3 receptor is beneficial. Thus, the compounds may find use eg in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.
The invention relates to a compound of the general formula (I): 
wherein
R1 represents
hydrogen,
C1-8-alkyl, C3-8-alkenyl or C3-8-alkynyl, which may optionally be substituted with one or more halogen atoms,
C3-7-cycloalkyl, C3-7-cycloalkenyl, C4-8-bicycloalkyl, C3-7-cycloalkyl-C1-3-alkyl or C3-7-cycloalkenyl-C1-3-alkyl, which may optionally be substituted at any position with one or more halogen-atoms,
R2 represents C1-6-alkyl,
f is 0, 1 or 2,
X represents xe2x80x94(CH2)mxe2x80x94(Z)nxe2x80x94(CH2)oxe2x80x94,
m and o independently are 0, 1, 2, 3 or 4,
n is 0 or 1,
Z is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH(Oxe2x80x94C1-6-alkyl)-, xe2x80x94C(xe2x95x90Nxe2x80x94OH)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94,
Y is
(a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, xe2x80x94NR3R4 and xe2x80x94O(Cxe2x95x90O)NR3R4, or wherein two substituents in adjacent positions form a radical xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94Oxe2x80x94,
wherein R3 and R4 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
aryl, aryloxy, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, xe2x80x94NR5R6 and xe2x80x94O(Cxe2x95x90O)NR5R6, or wherein two substituents in adjacent positions form a radical xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94Oxe2x80x94,
wherein R5 and R6 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
(b) C3-8-cycloalkyl or C5-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from
C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,
aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, xe2x80x94NR7R8 and xe2x80x94O(Cxe2x95x90O)NR7R8, or wherein two substituents in adjacent positions form a radical xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94Oxe2x80x94,
wherein R7 and R8 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof,
with the proviso that,
when m, n, and o are 0, R1 must not be cyclopentyl, cyclohexyl, ethyl, or methyl,
and with the proviso that the compound must not be 
Definitions
In the structural formulae given herein and throughout the present specification, the following terms have the indicated meaning:
The term xe2x80x9chalogenxe2x80x9d means F, Cl, Br or I.
The term xe2x80x9cC1-6-alkylxe2x80x9d as used herein represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Typical C1-6-alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
In the same way the terms xe2x80x9cC1-3-alkylxe2x80x9d and xe2x80x9cC1-8-alkylxe2x80x9d as used herein represent saturated, branched or straight hydrocarbon groups having from 1 to 3 carbon atoms and from 1 to 8 carbon atoms, respectively.
The term xe2x80x9cC3-8-alkenylxe2x80x9d as used herein represents a branched or straight hydrocarbon group having from 3 to 8 carbon atoms and at least one double bond. Typical C3-8-alkenyl groups include, but are not limited to, 1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 2-heptenyl, 2-octenyl, 1-ethylprop-2-enyl, 1,1-(dimethyl)prop-2-enyl, 1-ethylbut-3-enyl, 1,1-(dimethyl)but-2-enyl, 1,1-(dimethyl)pent-3-enyl, 1-ethylpent-2-enyl, 1,1-(dimethyl)pent-3-enyl, 1,1-(dimethyl)hex-3-enyl, 1-ethylhex-4-enyl and the like.
The term xe2x80x9cC3-8-alkynylxe2x80x9d as used herein represents a branched or straight hydrocarbon group having from 3 to 8 carbon atoms and at least one triple bond. Typical C3-8-alkynyl groups include, but are not limited to, 1-propynyl, 2-propynyl, isopropynyl, 1,3-butadiynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 2-heptynyl, 2-octynyl, 1-ethylprop-2-ynyl, 1,1-(dimethyl)prop-2-ynyl, 1-ethylbut-3-ynyl, 1,1-(dimethyl)but-2-ynyl, 1,1-(dimethyl)pent-3-ynyl, 1-ethylpent-2-ynyl, 1,1-(dimethyl)pent-3-ynyl, 1,1-(dimethyl)hex-3-ynyl, 1-ethylhex-4-ynyl and the like.
The term xe2x80x9cC1-6-alkoxyxe2x80x9d as used herein refers to the radical xe2x80x94Oxe2x80x94C1-6-alkyl, wherein C1-6-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term xe2x80x9cC1-6-alkanoylxe2x80x9d as used herein refers to the radical xe2x80x94C(xe2x95x90O)H or xe2x80x94C(xe2x95x90O)C1-5-alkyl, wherein C1-5-alkyl represents a saturated, branched or straight hydrocarbon groups having from 1 to 5 carbon atoms. Representative examples are acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, and the like.
The term xe2x80x9cC1-6-alkylthio as used herein refers to the radical xe2x80x94Sxe2x80x94C1-6-alkyl, wherein C1-6-alkyl represents a saturated, branched or straight hydrocarbon groups having from 1 to 6 carbon atoms as defined above. Representative examples are methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, and the like
The term xe2x80x9cC1-6-alkylsulfonylxe2x80x9d as used herein refers to the radical xe2x80x94S(xe2x95x90O)2xe2x80x94C1-6-alkyl, wherein C1-6-alkyl represents a saturated, branched or straight hydrocarbon groups having from 1 to 6 carbon atoms as defined above. Representative examples are methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, and the like.
The term xe2x80x9cC3-7-cycloalkylxe2x80x9d as used herein represents a saturated, monocyclic, carbocyclic group having from 3 to 7 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
The term xe2x80x9cC3-7-cycloalkenylxe2x80x9d as used herein represents a monocyclic, carbocyclic, non-aromatic group having from 3 to 7 carbon atoms and at least one double bond. Representative examples are cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.
In the same way the term xe2x80x9cC5-8-cycloalkenylxe2x80x9d as used herein represent a monocyclic, carbocyclic, non-aromatic group having from 5 to 8 carbon atoms and at least one double bond.
The term xe2x80x9cC4-8-bicycloalkylxe2x80x9d as used herein represents a saturated, bicyclic, carbocyclic group having from 4 to 8 carbon atoms. Representative examples are bicyclo-[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl and the like.
The term xe2x80x9carylxe2x80x9d as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.
The term xe2x80x9caryloxyxe2x80x9d as used herein refers to the radical xe2x80x94O-aryl, wherein aryl is as defined above. Non-limiting examples are phenoxy, naphthoxy, anthracenyloxy, phenantrenyloxy, fluorenyloxy, indenyloxy and the like.
The term xe2x80x9cheteroarylxe2x80x9d as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indanyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
xe2x80x9cAryl-C1-6-alkylxe2x80x9d, xe2x80x9caryl-C1-6-alkoxyxe2x80x9d etc. mean C1-6-alkyl or C1-6-alkoxy as defined above, substituted by aryl as defined above, for example: 
The term xe2x80x9coptionally substitutedxe2x80x9d as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.
The term xe2x80x9ctreatmentxe2x80x9d as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition. The patient to be treated is preferably a mammal, in particular a human being.
In one embodiment, Y is
(a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, xe2x80x94NR3R4 and xe2x80x94O(Cxe2x95x90O)NR3R4, or wherein two substituents in adjacent positions form a radical xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94Oxe2x80x94,
wherein R3 and R4 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
aryl, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, xe2x80x94NR5R6 and xe2x80x94O(Cxe2x95x90O)NR5R6, or wherein two substituents in adjacent positions form a radical xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94Oxe2x80x94,
wherein R5 and R6 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
(b) C3-8-cycloalkyl or C5-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from
C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,
aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, xe2x80x94NR7R8 and xe2x80x94O(Cxe2x95x90O)NR7R8, or wherein two substituents in adjacent positions form a radical xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94Oxe2x80x94,
wherein R7 and R8 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
In another embodiment, f is 1.
In another embodiment, R1 is C1-8-alkyl, C3-7-cycloalkyl-C1-3-alkyl or C3-7-cycloalkyl, which may optionally be substituted with one or more halogen atoms,
In still another embodiment, R1 is C1-8-alkyl, C3-7-cycloalkyl-C1-3-alkyl or C3-7-cycloalkyl, such as 1-ethylpropyl, 2-propyl, cyclobutyl or cyclopentyl.
In yet another embodiment, R2 is methyl.
In a further embodiment, X is xe2x80x94(CH2)mxe2x80x94C(xe2x95x90O)xe2x80x94CH2)oxe2x80x94, xe2x80x94(CH2)mxe2x80x94, a valence bond or xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)oxe2x80x94, wherein m and o are as defined for formula (I).
In yet a further embodiment, X is xe2x80x94(CH2)mxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94(CH2)mxe2x80x94, a valence bond or xe2x80x94CHxe2x95x90CHxe2x80x94, wherein m is 1, 2, 3 or 4, such as xe2x80x94(CH2)2xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, a valence bond or xe2x80x94CHxe2x95x90CHxe2x80x94.
In still a further embodiment, X is xe2x80x94(CH2)mxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94(CH2)mxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94, wherein m is 1, 2, 3 or 4, such as xe2x80x94(CH2)2xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94.
In another embodiment, Y is aryl, such as phenyl, which may optionally be substituted as defined for formula (I).
In still another embodiment, Y is phenyl, which may optionally be substituted with one or two of
C1-6-alkoxy, xe2x80x94NR3R4, halogen, trifluoromethyl or hydroxy, wherein R3 and R4 are as defined for formula (I),
two substituents in adjacent positions forming a radical xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94Oxe2x80x94, or
phenyl or phenoxy, which may optionally be substituted as defined for formula (I).
In yet another embodiment, Y is phenyl, which may optionally be substituted with one or two of
C1-6-alkoxy, xe2x80x94NR3R4, halogen, trifluoromethyl or hydroxy, wherein R3 and R4 independently are hydrogen or C1-6-alkyl,
two substituents in adjacent positions forming a radical xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, or
phenyl or phenoxy.
In another embodiment the invention relates to a compound of the general formula (I1): 
wherein R1, R2 and Y are as defined for formula (I) or any of the above embodiments.
In still another embodiment the invention relates to a compound of the general formula (I2): 
In yet another embodiment the invention relates to a compound of the general formula (I3): 
In still a further embodiment, the compound is selected from
4-(3,4-dimethoxyphenyl)-N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-N-methyl-4-oxobutyramide,
2-(4-dimethylaminophenyl)-N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-N-methylacetamide,
2-biphenyl-4-yl-N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-N-methylacetamide,
4-(4-chlorophenyl)-N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-N-methyl-4-oxobutyramide,
N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-N-methyl-3-(4-trifluoromethylphenyl)propionamide,
N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-N-methyl-3-phenoxybenzamide,
4-(3,4-dimethoxyphenyl)-N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-4-oxobutyramide,
N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-2-(3-fluoro-4-hydroxyphenyl)-N-methylacetamide,
2-biphenyl-4-yl-N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-N-methylacetamide,
2-biphenyl-4-yl-N-(1-cyclopentylpyrrolidin-3-yl)-N-methylacetamide,
3-benzo[1,3]dioxol-5-yl-N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-N-methylacrylamide,
3-(3-chlorophenyl)-N-[1-(1-ethylpropyl)pyrrolidin-3-yl]-N-methylacrylamide,
2-biphenyl-4-yl-N-(1-isopropylpyrrolidin-3-yl)-N-methylacetamide,
2-biphenyl-4-yl-N-(1-methylpyrrolidin-3-yl)-N-methylacetamide,
2-(3-fluorobiphenyl-4-yl)-N-(1-isopropylpyrrolidin-3-yl)-N-methylacetamide,
2-(2-fluorobiphenyl-4-yl)-N-(1-isopropylpyrrolidin-3-yl)-N-methylacetamide,
2-(2xe2x80x2-fluorobiphenyl-4-yl)-N-(1-isopropylpyrrolidin-3-yl)-N-methylacetamide,
2-(3xe2x80x2-fluorobiphenyl-4-yl)-N-(1-isopropylpyrrolidin-3-yl)-N-methylacetamide 2-(4xe2x80x2-fluorobiphenyl-4-yl)-N-(1-isopropylpyrrolidin-3-yl)-N-methylacetamide,
N-(1-Isopropylpyrrolidin-3-yl)-N-methyl-3-(4-trifluoromethylphenyl)acrylamide
2-Biphenyl-4-yl-N-(1-isopropyl-piperidin-3-yl)-N-methyl-acetamide
2-Biphenyl-4-yl-N-(1-cyclopropylmethyl-piperidin-3-yl)-N-methyl-acetamide
N-(1-Isopropyl-piperidin-3-yl)-N-methyl-3-phenoxy-benzamide
N-(1-Cyclopropylmethyl-piperidin-3-yl)-N-methyl-3-phenoxy-benzamide
3-Benzo[1,3]dioxol-5-yl-N-(1-isopropyl-piperidin-3-yl)-N-methyl-acrylamide
3-Benzo[1,3]dioxol-5-yl-N-(1-cyclopropylmethyl-piperidin-3-yl)-N-methyl-acrylamide
as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
The compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention.
Furthermore, when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention.
Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention.
The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds are able to form.
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
The compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
The compounds of the present invention interact with the histamine H3 receptor and are accordingly useful for the treatment of a wide variety of conditions and disorders in which histamine H3 receptor interactions are beneficial.
Accordingly, in another aspect the present invention relates to a compound of the general formula (I) as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for use as a pharmaceutical composition.
The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula (I) or any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
Furthermore, the invention relates to the use of a compound of the general formula (Ixe2x80x2): 
wherein
R1 represents
hydrogen,
C1-8-alkyl, C3-8-alkenyl or C3-8-alkynyl, which may optionally be substituted with one or more halogen atoms,
C3-7-cycloalkyl, C3-7-cycloalkenyl, C4-8-bicycloalkyl, C3-7 cycloalkyl-C1-3-alkyl or C3-7-cycloalkenyl-C1-3-alkyl,
which may optionally be substituted at any position with one or more halogen atoms,
R2 represents C1-6-alkyl,
X represents xe2x80x94(CH2)mxe2x80x94(Z)nxe2x80x94(CH2)oxe2x80x94,
m and o independently are 0, 1, 2, 3 or 4,
n is 0 or 1,
Z is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94C(xe2x95x90Nxe2x80x94OH)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94,
Y is
(a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, xe2x80x94NR3R4 and xe2x80x94O(Cxe2x95x90O)NR3R4, or wherein two substituents in adjacent positions form a radical xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94Oxe2x80x94,
wherein R3 and R4 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R3 and R4 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
aryl, aryloxy, aryl-C1-6-alkyl and aryl-C1-6-alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, xe2x80x94NR5R6 and xe2x80x94O(Cxe2x95x90O)NR5R6, or wherein two substituents in adjacent positions form a radical xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94Oxe2x80x94,
wherein R5 and R6 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
(b) C3-8-cycloalkyl or C5-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from
C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,
aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from
halogen, nitro, cyano, hydroxy, C1-6-alkanoyl, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, trifluoromethyl, trifluoromethoxy, xe2x80x94NR7R8 and xe2x80x94O(Cxe2x95x90O)NR7R8, or wherein two substituents in adjacent positions form a radical xe2x80x94Oxe2x80x94(CH2)1-3xe2x80x94Oxe2x80x94,
wherein R7 and R8 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C1-6-alkanoyl or aryl, or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated azetidinyl, pyrrolidinyl, piperidyl or azepanyl ring,
a well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of disorders and diseases related to the histamine H3 receptor.
In still another aspect, the invention relates to a method for the treatment of diseases and disorders related to the histamine H3 receptor the method comprising administering to a subject in need thereof an effective amount of a compound of the formula (I) or any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
In one aspect the invention relates to compounds with histamine H3 receptor antagonistic activity or inverse agonistic activity which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor blockade is beneficial.
In another aspect the invention relates to compounds with histamine H3 receptor agonistic activity and which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor activation is beneficial.
In one embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the reduction of weight.
In another embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment of overweight or obesity.
In still another embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the suppression of appetite or satiety induction.
In a further embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes, especially type 2 diabetes (NIDDM (non-insulin dependent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon cancers.
In yet a further embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.
In a further embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment of IGT.
In a further embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes. Such treatment includes inter alia treatment for the purpose of delaying or prevention of the progression from IGT to type 2 diabetes as well as delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
The compounds of the present invention may also be used for the treatment of airway disorders such as asthma, as anti-diarrhoeals and for the modulation of gastric acid secretion.
Furthermore, the compounds of the present invention may be used for the treatment of diseases associated with the regulation of sleep and wakefulness and for the treatment of narcolepsy and attention deficit disorder.
Moreover, the compounds of the invention may be used as CNS stimulants or as sedatives.
The present compounds may also be used for the treatment of conditions associated with epilepsy. Additionally, the present compounds may be used for the treatment of motion sickness and vertigo. Furthermore, they may be useful as regulators of hypothalamohypophyseal secretion, antidepressants, modulators of cerebral circulation, and in the treatment of irritable bowel syndrome.
Further, the compounds of the present invention may be used for the treatment of dementia and Alzheimer""s disease.
The compounds of the present invention may also be useful for the treatment of allergic rhinitis, ulcer or anorexia.
The compounds of the present invention may furthermore be useful for the treatment of migraine, see McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 (1998), 43-50, and for the treatment of myocardial infarction, see Mackins et al., Expert Opinion on Investigational Drugs 9 (2000), 2537-2542.
In a further aspect of the invention treatment of a patient with the present compounds is combined with diet and/or exercise.
In a further aspect of the invention the present compounds are administered in combination with one or more further active substances in any suitable ratio(s). Such further active agents may be selected from antiobesity agents, antidiabetics, antidyslipidemic agents, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or associated with obesity.
Thus, in a further aspect of the invention the present compounds are administered in combination with one or more antiobesity agents or appetite regulating agents.
Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, xcex23 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or citalopram, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin or placental lactogen, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X receptor) modulators, TR xcex2 agonists, AGRP (Agouti related protein) inhibitors, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.
In one embodiment of the invention the antiobesity agent is leptin.
In another embodiment the antiobesity agent is dexamphetamine or amphetamine.
In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine.
In still another embodiment the antiobesity agent is sibutramine.
In a further embodiment the antiobesity agent is orlistat.
In another embodiment the antiobesity agent is mazindol or phentermine.
In still another embodiment the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.
In yet another embodiment the antiobesity agent is growth hormone, a growth factor such as prolactin or placental lactogen, or a growth hormone releasing compound.
In yet a further aspect the present compounds are administered in combination with one or more antidiabetic agents.
Relevant antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 0 792 290 (Novo Nordisk A/S), eg Nxcex5B29-tetradecanoyl des (B30) human insulin, EP 0 214 826 and EP 0 705 275 (Novo Nordisk A/S), eg AspB28 human insulin, U.S. Pat. No. 5,504,188 (Eli Lilly), eg LysB28 ProB29 human insulin, EP 0 368 187 (Aventis), eg Lantus(copyright), which are all incorporated herein by reference, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycaemic agents.
The orally active hypoglycaemic agents preferably comprise imidazolines, sulfonylureas, biguamides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, xcex1-glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the xcex2-cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists, such as ALRT-268, LG-1268 or LG-1069.
In one embodiment of the invention the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as Nxcex5B29-tetradecanoyl des (B30) human insulin, AspB28 human insulin, LysB28 ProB29 human insulin, Lantus(copyright), or a mix-preparation comprising one or more of these.
In a further embodiment of the invention the present compounds are administered in combination with a sulfonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, gliclazide or glyburide.
In another embodiment of the invention the present compounds are administered in combination with a biguamide eg metformin.
In yet another embodiment of the invention the present compounds are administered in combination with a meglitinide eg repaglinide or nateglinide.
In still another embodiment of the invention the present compounds are administered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy""s Research Foundation), which are incorporated herein by reference.
In still another embodiment of the invention the present compounds may be administered in combination with an insulin sensitizer eg such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy""s Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S), which are incorporated herein by reference.
In a further embodiment of the invention the present compounds are administered in combination with an xcex1-glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
In another embodiment of the invention the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the xcex2-cells eg tolbutamide, glibenclamide, glipizide, gliclazide, BTS-67582 or repaglinide.
In yet another embodiment of the invention the present compounds may be administered in combination with nateglinide.
In still another embodiment, the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent, eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
In still another embodiment of the invention the present compounds are administered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
In another aspect of the invention, the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combination with metformin and a sulfonylurea such as glyburide; a sulfonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.
Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are xcex2-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and xcex1-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
It should be understood that any suitable combination of the compounds according to the invention with diet and/or exercise, one or more of the above-mentioned compounds and optionally one or more other active substances are considered to be within the scope of the present invention.
Pharmaceutical Compositions
The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet, which may be prepared by conventional tabletting techniques, may contain:
If desired, the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.